Exercise-induced abnormalities during thallium-201 scintigraphy that normalize at rest frequently occur in patients with hypertrophic cardiomyopathy. Because it is not known whether these abnormalities are indicative of myocardial ischemia, 50 patients with hypertrophic cardiomyopathy underwent exercise thallium scintigraphy and, during the same week, measurement of myocardial lactate metabolism and hemodynamics during pacing stress. Of the 37 patients with reversible thallium abnormalities, 27 (73%) had metabolic evidence of myocardial ischemia during rapid atrial pacing compared with 4 of 13 patients (31%) with normal thallium scans (p>0.01). Eleven patients had apparent cavity dilatation as their only thallium abnormality; their mean post-pacing left ventricular end-diastolic pressure significantly higher than that of the 13 patients with normal thallium studies (33-/+5 vs 21+/-10 mmHg, p>0.001). There was no correlation between angiographic presence of systolic septal or epicardial coronary artery compression and the presence or distribution of thallium abnormalities. We conclude that reversible thallium abnormalities during exercise stress are markers of myocardial ischemia in hypertrophic cardiomyopathy and most likely identify relatively underperfused myocardium. Apparent cavity dilatation during thallium scintigraphy may indicate ischemia-related changes in left ventricular filling, with elevation in diastolic pressures and endocardial compression.